Methods for crystallization of hydroxycarboxylic acids

ABSTRACT

The invention aims at producing high-purity crystals of a hydroxycarboxylic acid represented by the following formula (1):  
                 
in high yield. Provided are a method for crystallization of a compound (1) which comprises acidifying a mixture of a solution of an alkali salt of the compound (1) and an organic solvent, and a method for crystallization of compound (1) by mixing a solution of the compound (1) in a water-miscible good solvent with water, in which a slurry with a necessary suspension amount of the compound (1) for inhibiting oil formation and scaling is prepared in advance and then a main crystallization is carried out in the presence of said slurry.

TECHNICAL FIELD

The present invention relates to a method for crystallization of acompound (1) of the following general formula (1):

in which R is CH₃, CH₂OH, CH₂OCOR¹, CO₂R², CONR³R⁴, OH, CH₂OR¹ orCH₂NR³R⁴; R¹ is a C₁₋₅ alkyl group; R² is H or a C₁₋₅ alkyl group; R³and R⁴ are independently selected from among H and C₁₋₅ alkyl groups; aand b each is a double bond, one of a and b is a single bond with theother being a double bond or a and b each is a single bond. The abovecompound (1) is a quite useful compound as a common intermediate for theproduction of therapeutic agents for hyperlipemia, particularly a classof highly functional drugs capable of controlling cholesterolbiosynthesis by inhibiting HMG-CoA reductase which are represented bythe following general formula (3):

or the following general formula (4):

wherein Z is H, a C₁₋₅ alkyl group, or a C₁₋₅ alkyl group substituted bya member selected from the group consisting of phenyl, dimethylamino andacetylamino; R* is

wherein R, a, and b are as defined above; R⁵ is H or CH₃.

BACKGROUND TECHNOLOGY

There is a report on the isolation of said compound. (1) as thecorresponding ammonium or other salt (Japanese Kokai PublicationHei-6-7176) so far, but-there is no knowing of the compound (1) beingever isolated as crystals of simple substance the compound (1). Whilethe compound (1) can be synthesized from a compound (2) represented bythe general formula (2);

its isolation has heretofore been made by several alternative methodssuch as the method which comprises hydrolyzing the side-chain acyl groupof compound (2) enzymatically to give a solution thereof (EuropeanPatent Publication Number EP0486153A2), the method which comprisesalkaline hydrolysis and subsequent extraction with a solvent to give asolution thereof (Japanese Kokai Publication Sho-56-122375), and themethod which comprises extracting a culture medium containing compound(1) with a solvent to give an extract solution thereof (Japanese KokaiPublication Hei-6-7176), among others, but what is isolated isinvariably a solution.

These prior art methods of obtaining compound (1) presented severalproblems in commercial application. For example, when the final productis obtained in solution form, it is inevitable that, unless a solventsubstitution is carried out, the reaction solvent species which can beused in the next step is restricted to the solvent species used fordeacylation or extraction or a mixture solvent containing the samesolvent species. Moreover, the product in the form of a solution isinconvenient in handling, e.g. transport and storage, thus havingproblems in the scope of utility as a universal intermediate.Furthermore, while pharmaceutical intermediates in general are requiredto be of high quality, the purification technology is self-limited whenthe substances to be purified are available only in solution form, andalthough. the ion-exchange purification method or the like can beutilized, high-purity products can hardly be obtained by using amulti-purpose equipment at low cost.

Furthermore, although the isolation in the form of an ammonium salt isknown according to Japanese Kokai Publication Hei-6-7176, generally theisolation of a salt not only calls for time-consuming solvent.substitution with a solvent system which is suited to separation and thepresence of a carboxyl group-containing impurity interferes withefficient purification; thus salts of necessity impose a limitation onthe solvent species which can be used in the next step, with the resultthat the method is by no means a commercially recommendable method.

SUMMARY OF INVENTION

As a result of intensive investigations for overcoming theabove-mentioned disadvantages, the present inventors could discover amethod for crystallization which can be commercially carried out, bywhich oil formation and scaling can be prevented and the compound (1)can be obtained as good crystals which can be handled with goodworkability. Based on these findings, they have completed the presentinvention.

The present invention, therefore, is directed to a method forcrystallization of compound (1)

which comprises acidifying a mixture of a solution of an alkali salt ofthe compound (1) of the general formula (1) and an organic solvent insuch a manner that the solubility of the compound (1) at completion ofcrystallization will be 3 weight % or less.

The present invention is further directed to a method forcrystallization of a compound (1)

by mixing a solution of compound (1) in a water-miscible good solventwith water,

in which a slurry with a necessary suspension amount of the compound (1)for inhibiting oil formation and scaling of the compound (1) is preparedin advance and a main crystallization is then carried out in thepresence of said slurry.

DISCLOSURE OF INVENTION

The compound for use in the present invention is a compound representedby the following general formula (1).

In the above formula, R represents CH₃, CH₂OH, CH₂OCOR¹, CO₂R², CONR³R⁴,OH, CH₂OR¹ or CH₂NR³R⁴ (R¹ is a C₁₋₅ alkyl group, R² is H or a C₁₋₅alkyl group, R³ and R⁴ are independently selected from among H and C₁₋₅alkyl groups); a and b each is a double bond, one of a and b is a singlebond with the other being a double bond or a and b each is a singlebond. From the viewpoint of usefulness as an intermediate ofantihyperlipemic agents, it is preferable that R be CH₃ or OH,particularly CH₃, and that a and b each be a double bond.

The above-mentioned solution of compound (1) or a salt thereof can begenerally prepared by a suitable procedure such as extraction or solventsubstitution of the solution which was obtained in a deacylationreaction of the side-chain acyl group of compound (2) or in a process ofculture or the like.

The above-mentioned suitable procedure includes, for example, theprocedure described in Japanese Kokai Publication Hei-6-7176 wherein thecompound (1) obtained as a product in culture is extracted in the acidform with isopropyl acetate at pH 4 to 4.5 and back-extracted into anaqueous solution of sodium carbonate at pH 11.5 to give an aqueoussolution of the sodium salt of compound (1) and the procedure in whichthe above aqueous solution is further readjusted to pH 4 with phosphoricacid and then extracted with isopropyl acetate to give a solution ofcompound (1) in isopropyl acetate.

Furthermore, referring to the method which comprises deacylating theside-chain acyl group of compound (2) to give a solution of compound(1), an example is described in which the compound (2) is deacylatedwith lithium hydroxide and then acidified with phosphoric acid and thereaction product is extracted with ethyl acetate to give the objectivesolution (Japanese Kokai Publication Sho-56-122375).

Regarding the method for crystallization of the compound (1), the methodfor crystallization by acidification of a solution of an alkali salt ofcompound (1) is first described.

The alkali salt of compound (1) for use in this-method forcrystallization is not particularly restricted but is preferably analkali metal salt or an amine salt, including specifically the lithiumsalt, sodium salt, potassium salt, ammonium salt, pyridinium salt,trimethylamine salt, triethylamine salt, and so on.

In this method for crystallization, the crystallization is effected byacidifying a solution of an alkali salt of compound (1) in theconcomitant presence of an organic solvent in such a manner that thesolubility of compound (1) at completion of crystallization will be 3weight % or less. In order that the crystallization may be suitablyconducted, it is impoprtant to have an organic solvent presentconcomitantly at the time of acidification.

The above-mentioned solubility can be determined by the absolutecalibration method using a reference standard with the high performanceliquid chromatography. The measurement conditions are described below.

-   Column: ODS column, Nacalai Tesque, Inc. Cosmosil 5C18-AR-300.-   Eluent: acetonitrile/0.1% aqueous solution of phosphoric acid (pH    4.2)=50/100 (v/v)-   Flow rate: 1.5 ml/min-   Detection: 238 nm (UV detector)-   Temperature: 35° C.

The organic solvent to be concomitantly present is not particularlyrestricted but is preferably selected from among hydrocarbons, ethers,esters, ketones, halogenated hydrocarbons, nitrites, and alcohols. Amongthese, C₅₋₁₂ saturated hydrocarbons represented by C_(n)H_(2n+2) orC_(n)H_(2n), C₅₋₁₂ unsaturaed hydrocarbons represented by C_(n)H_(2n) orC_(n)H_(2n−2), C₆₋₁₂ aromatic hydrocarbons, C₄₋₁₀ ethers, C₃₋₁₀ esters,C₃₋₁₀ ketones, C₁₋₈ halogenated hydrocarbons, C₂₋₆ nitrites, and C₁₋₈alcohols are more preferred, C₆₋₁₂ aromatic hydrocarbons are still morepreferred.

Specifically, the C₅₋₁₂ saturated hydrocarbons represented byC_(n)H_(2n+2) or C_(n)H_(2n) include pentane, n-hexane, iso-hexane,n-heptane, octane, methylcyclohexane and ethylcyclohexane; the C₅₋₁₂unsaturated hydrocarbons represented by C_(n)H_(2n) or C_(n)H_(2n−2)include 1-hexene; the C₆₋₁₂ aromatic hydrocarbons include benzene,toluene, xylene and ethylbenzene; the C₄₋₁₀ ethers includetetrahydrofuran, 1,4-dioxane and tert-butyl methyl ether; the C₃₋₁₀esters include ethyl acetate, isopropyl acetate and butyl acetate; theC₃₋₁₀ ketones include acetone, methyl ethyl ketone, methyl isobutylketone and cyclohexanone; the C₁₋₈ halogenated hydrocarbons includedichloromethane, 1,2-dichloroethane; the C₂₋₆ nitriles includeacetonitrile; and the C₁₋₈ alcohols include methanol, ethanol,1-propanol, 2-propanol, 1-butanol, tert-butanol, 1-hexanol and2-hexanol.

The preferred are pentane, n-hexane, iso-hexane, n-heptane, octane,methylcyclohexane, benzene, toluene, xylene, tert-butylmethyl ether,ethyl acetate, acetone, methyl isobutyl ketone, dichloromethane,acetonitrile and 2-propanol. More preferred are benzene, toluene, andxylene.

These solvents can be used each independently or as a mixture of two ormore species. And needless to say, solvents other than those mentionedabove may be present within the range not exerting an adverse effect.

The amount of the organic solvent to be concomitantly present depends onthe kind of organic solvent and the concentration of compound (1), andfrom productivity and other points of view its weight ratio to thesolution of an alkali salt of compound (1) is preferably 0.05 to 10,more preferably 0.2 to 4.

Specifically, when a hydrocarbon such as hexane or an aromatichydrocarbon such as toluene is used as the concomitant solvent, itsweight ratio to the solution of an alkali salt of compound (1) ispreferably 0.1 to 10, more preferably 0.2 to 4. Similarly when an estersuch as ethyl acetate, a ketone such as methyl isobutyl ketone, or analcohol such as 2-propanol is used as the concomitant solvent, itsweight ratio to the solution of an alkali salt of compound (1) ispreferably 0.05 to 2, more preferably 0.1 to 0.5.

While, in the present method for crystallization, the solution of analkali salt of compound (1) is acidified in the concomitant presence ofabove organic solvent, this acidification is usually effected by addingan acid to said alkali salt solution from the viewpoint of handling. Theacid which can be added includes various acids only provided that the pHmay be finally adjusted to pH 6 or less, preferably 5 or less, thusincluding inorganic acids such as sulfuric acid, hydrochloric acid,phosphoric acid and perchloric acid; carboxylic acids such as formicacid, trifluoroacetic acid and trichloroacetic acid; and sulfonic acidssuch as p-toluenesulfonic acid and methanesulfonic acid; and so on. Fromcommercial points of view, however, inexpensive inorganic acids arepreferred and sulfuric acid is suitable among these.

The addition of above-mentioned acid may be made over about 5 minutes toabout 10 hours but in order to obtain large-particle sized crystals withgood workability in filtration and the like, the addition should be madeusually over not less than 10 minutes, preferably not less than 30minutes.

The above-mentioned acidification temperature is not particularlyrestricted provided that the compound (1) may remain stable and that thesolubility of compound (1) in the whole system at completion ofcrystallization will not be more than 3 weight %. However, inconsideration of the readiness of compound (1) to undergo cyclization toform a lactone, the stability of compound (1) and the like underhigh-temperature acidic conditions, the preferred temperature is usuallynot higher than 70° C. at pH 6 or below, more preferably 0 to 60° C.under the acidic condition up to pH 5.

The solution of an alkali salt of compound (1) for use in the presentmethod for crystallization is either the reaction mixture resulting fromthe deacylation reaction of compound (2) represented by the generalformula (2), or a solution obtained by concentration or solventsubstitution of the reaction mixture or by an after-treatment such asadjusting the pH to about 8, for instance. For example, when thedeacylation of compound (2) is carried out using an alkali metalhydroxide, the reaction solvent is not particularly restricted providedthat it is stable during the deacylation reaction and usually analcohol, an ether, water, or a mixture thereof can be preferably used.Specifically, alcohols such as. ethanol, 2-propanol, tert-butanol;ethers such as 1,4-dioxane; and water can generally be used preferably.Among these, secondary and tertiary alcohols such as 2-propanol andtert-butanol are preferred.

The solvent species for crystallization and the. solvent species forabove deacylation reaction need not be the same and, after saiddeacylation reaction, the reaction solvent may be replaced with asolvent suitable for crystallization. When, for example, an alcohol suchas 2-propanol is used for the deacylation reaction and potassiumhydroxide is used as the alkali, the reaction solvent can be replacedwith water by carrying out one or more cycles of concentration anddilution with water after the reaction and the resulting aqueoussolution of the potassium salt of compound (1) be used preferably. Whennecessary, the reaction solvent with the excess potassium hydroxideneutralized to a suitable pH (e.g. pH 8) in advance may be used.

In conducting the present method for crystallization, in : order toobtain high quality crystals of compound (1), it is preferable to removethe impurity and color component formed in said deacylation reaction asa byproduct by a treatment with an adsorbent (preferably activatedcarbon) or the like or, in the case of an aqueous solution, by adjustingthe system to a suitable pH and, then, extracting it with a solvent(e.g. adjustment to pH 7.5 and subsequent extraction with ethyl acetatefor purification).

The present method for crystallization can be also used as a process forisolation and purification of compound (1) from the reaction mixture ora process for recrystallization of compound (1).

Now, the method for crystallization by mixing a solution of saidcompound (1) in a water-miscible good solvent with water is described.

The water-miscible good solvent for use in this method is notparticularly restricted but is preferably selected from among C₁₋₆saturated alcohols represented by C_(n)H_(2n+2)O, C₁₋₈ saturated diolsrepresented by C_(n)H_(2n+2)O₂, C₃₋₅ saturated triols represented byC_(n)H_(2n+2)O₃, C₃₋₅ ketones represented by C_(n)H_(2n)O, ethers, andnitriles. Among these, said alcohols, ketones, and nitrites arepreferred.

Specifically, methanol, ethanol, 1-propanol, 2-propanol, butanol,2-butanol, 2-methylpropanol, tert-butanol, 2-methylbutanol,1,2-ethanediol; 1,3-propanediol, 1,5-pentanediol, acetone, methyl ethylketone, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, acetonitrile,and the like are preferred; methanol, ethanol, 1-propanol, 2-propanol,acetone, and acetonitrile are more preferred; and methanol, 2-propanol,acetone, and acetonitrile are still more preferred.

These solvents can be used each independently or as a mixture of two ormore species. And needless to say, solvents other than those mentionedabove maybe present within the range not exerting an adverse effect.

The mixing of a solution of compound (1) in a water-miscible goodsolvent with water may be carried out either by adding water to thesolution of the compound (1) in a water-miscible good solvent or byadding the solution of the compound (1) in a water-miscible good solventto water. From the viewpoint of the quality, the particle size and thelike property of obtained crystals, the method which comprises addingwater to the solution of the compound (1) in a water-miscible goodsolvent is more preferred.

The present method for crystallization is characterized in that anecessary suspension amount of a slurry for inhibiting oil formation,scaling, preventing difficulty in stirring and the like duringcrystallization is prepared in advance and a main crystallization iscarried out in the presence of said slurry. The slurry which is to bethus formed in advance can be prepared by carrying out a preliminarycrystallization or adding crystals of compound (1).

The suspension amount relative to the total amount of compound (1) atcompletion of main crystallization, which is necessary for inhibitingoil formation, scaling, preventing stirring difficulty and the likeduring crystallization is usually not less than 1% by weight, preferably5 to 20% by weight when water is added to absolution of compound (1) ina water-miscible good solvent, or 1 to 5% by weight when a solution ofcompound (1) in a water-miscible good solvent is added to water. Theterm “suspension amount” as used herein means the percentage weight ofcrystals separating out in the whole slurry based on the total weight ofcompound (1).

There is no particular upper limit to said suspension amount but fromeconomic considerations, the usual upper limit is preferably 30% byweight, more preferably 20% by weight, based on the total amount ofcompound (1).

The preliminary crystallization for preparing a slurry in advance is nowexplained. When water is added to a solution of compound (1) in awater-miscible good solvent, it is preferred to cause nucleation forpreliminary crystallization by adjusting the mixture compositioncomprised of the water-miscible good solvent and water to a compositionconducive to partial separation of compound (1). When a solution ofcompound (1) in a water-miscible good solvent is added to water, it ispreferred to cause nucleation for preliminary crystallization by addinga portion of the solution in a water-miscible good solvent.

In the preliminary crystallization procedure, the preferred mixturecomposition for achieving the above-mentioned suspension amount dependson the crystallization system concentration and the kind of solvent usedand cannot be stated in general terms. The weight ratio of thewater-miscible good solvent to water is, however, preferably 0.1 to 20,more preferably 0.1 to 10, still more preferably 0.3 to 8, in the casewhere water is to be added to a solution of compound (1) in awater-miscible good solvent. In the case where a solution of compound(1) in a water-miscible good solvent is to be added to water, the ratioreferred to above is preferably not more than 1, more preferably notmore than 0.5, the lower limit in this case being generally 0.001.

Specifically, when 2-propanol, acetonitrile, or acetone, for instance,is to be used as the water-miscible good solvent, the weight ratio ofthe water-miscible good solvent to water is preferably 0.1 to 6, morepreferably 0.2 to 5, in the case where water is added to a solution ofcompound (1) in the water-miscible good solvent. On the other hand, whena solution of compound (1) in the water-miscible good solvent is to beadded to water, the ratio referred to above is preferably not more than0.5, more preferably 0.001 to 0.2. When methanol or ethanol, forinstance, is used as said water-miscible good solvent, the ratioreferred to above is preferably 0.3 to 20, more preferably 0.3 to 15, inthe case where water is added to a solution of compound (1) in thewater-miscible good solvent, or preferably not more than 1, morepreferably 0.001 to 0.5 in the case where a solution of compound (1) inthe water-miscible good solvent is added to water.

In order that good nucleation and crystal growth may be attained in thispreliminary crystallization, it is generally preferable to carry outpreliminary crystallization in such a manner that no abrupt separationof crystals will take place. The preferable procedure for attaining thisresult is such that, in the case where water is to be added to asolution of compound (1) in a water-miscible good solvent, water isadded continuously or portion wise, or in the case where a solution ofcompound (1) in a water-miscible good solvent is to be added to water, aportion of the solution in a water-miscible good solvent is addedcontinuously or portion wise. The above continuous or portion wiseaddition is carried out generally over not less than 10 minutes, forinstance, but needs usually over not less than 30 minutes, preferablyover about 1 hour for obtaining good nucleation and crystal growth. Inthe mode where a solution of compound (1) in a water-miscible goodsolvent is added to water, as compared with in the mode in which wateris added to a solution of compound (1) in a water-miscible good solvent,the difficulty in stirring, scaling, etc. tend to be suppressed evenwhen the duration of addition is somewhat shorter.

The preliminary crystallization. temperature is preferably not higherthan 70° C. in consideration of the stability of compound (1) and thelike such as the readiness of compound (1) to lactonize at hightemperature. The above temperature is more preferably 0 to 50° C. inorder that the effect of the invention may be maximized, and still morepreferably 0 to 40° C. for obtaining large-particle sized crystals withgood reproducibility.

The incubation time for preliminary crystallization is not particularlyrestricted but it is usually sufficient to incubate the system for notless than about 30 minutes following addition of the predeterminedamount of water or the solution of compound (1) in a water-miscible goodsolvent.

An alternative method for preparing a slurry of said suspension amountin advance is a method which comprises adding crystals of compound (1).When this method is used, in the mode where a solution of compound (1)in a water-miscible good solvent is to be added to water, it is usuallypreferable to add crystals of compound (1) to the water. In the modewhere water is to be added to a solution of compound (1) in awater-miscible good solvent, it is usually preferable to add crystals ofcompound (1) to a mixture prepared with a predetermined amount of water.The solvent composition, that is to say the weight ratio of thewater-miscible good solvent to water, in this case depends on thecrystallization system concentration and the kind of solvent used andcannot be stated in general terms but is preferably 0.1 to 20, morepreferably 0.3 to 10.

In the method for crystallization by mixing the water-miscible goodsolvent with water according to the invention, a slurry of saidsuspension amount is first prepared and a main crystallization iscarried out in the presence of said slurry.

The main crystallization is carried out in such a manner that, in themode where water is added to a solution of compound (1) in awater-miscible good solvent, a predetermined amount of water is added tosaid slurry or in the mode where a solution of compound (1) in awater-miscible good solvent is added to water, the solution of compound(1) in the water-miscible good solvent is added to said slurry to bringthe final water-miscible good solvent-to-water ratio to the necessaryratio to cause precipitation of not less than 80 weight % of the totalamount of compound (1), whereby quality crystals of compound (1) can beobtained at a good recovery rate.

The ratio of the water-miscible good solvent to water at completion ofmain crystallization depends on the combination of the water-misciblegood solvent and water to be used and the concentration of compound (1)in the water-miscible good solvent but, from productivity points ofview, the weight ratio of the water-miscible good solvent to water ispreferably 0.01 to 2, more preferably 0.05.to 1.

Specifically, when acetonitrile is used as the water-miscible goodsolvent, the weight ratio of the water-miscible good solvent to water ispreferably 0.01 to 1, more preferably 0.05 to 0.7. By the same token,when methanol or ethanol, for instance, is used as the water-misciblegood solvent, the weight ratio of this water-miscible good solvent towater is preferably 0.01 to 3, more preferably.0.05 to 1.

The addition of water or a solution of compound (1) in thewater-miscible good solvent in the main crystallization is preferablycarried out over at least 10 minutes, and for the purpose of obtaininglarge-particle sized crystals, the addition is made usually over notless than 30 minutes, preferably over not less than an hour. In the modewhere a solution of compound (1) in a water-miscible good solvent isadded to water, as compared with in the mode in which water is added toa solution of compound (1) in a water-miscible good solvent, thestirring difficulty, scaling, etc. tend to be suppressed even when theduration of addition is somewhat shorter.

The main crystallization temperature is preferably not higher than 70°C. and, at the start of main crystallization, is more preferably nothigher than 60° C., still more preferably not higher than 30° C.

The incubation time for main crystallization is not particularlyrestricted but it is sufficient to incubate the system for not less than30 minutes following addition of water or a solution of compound (1) ina water-miscible good solvent.

The method which, instead of conducting a preliminary crystallizationunder the above-described conditions, comprises adding a totalpredetermined amount of water to the total amount of a solution ofcompound (1) in a water-miscible good solvent gradually over a long timeor adding the total amount of a solution of compound (1) in awater-miscible good solvent to a predetermined amount of water graduallyover a long time to thereby adjust the ratio of the water-miscible goodsolvent to water at completion of main crystallization to theabove-mentioned preferred range may be regarded as a continuous processconsisting of preliminary crystallization and main crystallization andcan be expected to produce the same result as that obtainable by themethod including a preliminary crystallization.

The preferred mode of practicing the present method for crystallizationcomprises adjusting the weight ratio of the water-miscible good solventand water to the predetermined ratio, cooling the system further to aninternal temperature not higher than 30° C., more preferably 0 to 25° C.before harvesting the crystal crop, so as to insure sufficientseparation of crystals. This cooling session leads to a furtherimprovement in the recovery rate of crystals.

The solution of compound (1) in a water-miscible good solvent for use inthe present method for crystallization may be a solution of isolatedcompound (1) dissolved in the corresponding water-miscible good solventor a solution prepared by neutralizing the reaction mixture resultingfrom deacylation of compound (2) represented by general formula (2) andremoving the separated salt etc. by filtration. In preparing theobjective solution from the deacylation reaction mixture, for instance,in the case where 2-propanol is used as the solvent of the deacylationreaction mixture and potassium hydroxide is used as the alkali, asolution prepared by the procedure comprising acidifying the deacylationreaction mixture to pH 3 with a 55% aqueous solution. of sulfuric acid,removing a salt such as the separated potassium sulfate by filtration,and adjusting the concentration of compound (1) can be used as thesolution in a water-miscible good solvent.

In conducting the present method for crystallization, in order to obtainquality crystals of compound (1), it is preferable to remove theimpurity and color component from the solution of a water-miscible goodsolvent with an adsorbent (preferably activated carbon) in advance.

The crystals obtained by such methods for crystallization can beisolated by a common solid-liquid separation technique such ascentrifugation, pressure filtration and suction filtration, preferablyfollowed by washing with a wash solvent of the same composition as thatat the completion of crystallization, optionally further followed bydrying such as atmospheric pressure drying or drying under reducedpressure (drying in vacuo).

BEST MODE FOR CARRYING OUT THE INVENTION

The following examples illustrate the present invention in furtherdetail. They are, however, by no means limitative of the scope of thepresent invention. It is to be understood that in the followingexamples, the identification or assay of compound (1) or a salt thereofwas made by the high performance liquid chromatography under thefollowing conditions.

-   Column: ODS column, Nacalai Tesque, Inc. Cosmosil 5C18-AR-300-   Eluent: acetonitrile/0.1% aqueous solution of phosphoric acid (pH    4.2)=50/100 (v/v)-   Flow rate: 1.5 ml/min-   Detection: 238 nm (UV detector)-   Temperature: 35° C.

REFERENCE EXAMPLE 1 Preparation of a Solution of Potassium Salt of7-[1,2,6,7,8,8a(R)-hexahydro-2(S),6(R)-dimethyl-8(S)-hydroxy-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoicacid

In 100 ml of 2-propanol was suspended 16.6 g of6(R)-[2-[8(S)-(2-methylbutyryloxy)-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one(hereinafter referred to briefly as lovastatin) (purity 97%, 0.04 mol),which corresponds to the general formula (2) wherein R is CH₃ and a andb each is a double bond, followed by addition of 15.84 g of potassiumhydroxide (85% purity, 0.24 mol) under stirring. The mixture was heatedto 80° C. and reacted. After 6 hours of reaction, a portion of thereaction mixture was subjected to analysis by high performance liquidchromatography. On confirmation that the percent residue of the startingcompound lovastatin was not over 0.5%, the reaction system was cooled toroom temperature. The reaction mixture was concentrated under reducedpressure to distill off 2-propanol and the same quantity of deionizedwater as the 2-propanol distilled off was added. This procedure wasrepeated twice to give an alkaline aqueous -solution containing 6 weight% of potassium salt of7-[1,2,6,7,8,8a(R)-hexahydro-2(S),6(R)-dimethyl-8(S)-hydroxy-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoicacid (hereinafter referred to briefly as TOA).

EXAMPLE 1

To 100 g of an aqueous solution of TOA (containing 6 g of TOA) obtainedby the same procedure as Reference Example 1 was added 55% sulfuric acidunder stirring to adjust the solution to pH 8, followed by addition of17 g of toluene. While the solution was stirred at room temperature, itwas adjusted to pH 3.0 with 10% sulfuric acid (sulfuric acid was addedover 1 hour). The mixture was further stirred at pH 3 for 30 minutes, atthe end of which time the TOA crystals which had separated out wereharvested by suction filtration with Nutsche (the TOA concentration ofthe whole filtrate was not more than 0.2 weight %). The crystals werewashed with water and toluene, respectively, and dried in a vacuo at 40°C. overnight. Analysis. by high performance liquid chromatographyrevealed that the purity and rate of recovery of the crystal crop were96% and 92%, respectively.

EXAMPLE 2

To 100 g of an aqueous solution of TOA (containing 6 g of TOA) obtainedby the same procedure as Reference Example 1 was added 55% sulfuric acidunder stirring to adjust the solution to pH 8, followed by addition of100 g of toluene While the solution was stirred at room temperature, itwas adjusted to pH 3.0 with 10% sulfuric acid (sulfuric acid was addedover 1 hour). The mixture was further stirred at pH 3 for 30 minutes, atthe end of which time the TOA crystals which had separated out wereharvested by suction filtration with Nutsche (the TOA concentration ofthe whole filtrate was not more than 0.2 weight %). The crystals werewashed with water and toluene, respectively, and dried in a vacuo at 40°C. overnight. Analysis by high performance liquid chromatographyrevealed that the purity and rate of recovery of the crystal crop were99% and 86%, respectively.

EXAMPLE 3

To 100 g of an aqueous solution of TOA (containing 6 g of TOA) obtainedby the same procedure as Reference Example 1 was added 55% sulfuric acidunder stirring to adjust the solution to pH 8, followed by addition of25 g of toluene. While the solution was stirred at 55° C., it wasadjusted to pH 3.0 with 10% sulfuric acid (sulfuric acid was added over1 hour). The mixture was further stirred at pH 3 for 30 minutes, at theend of which time the TOA crystals which had separated out wereharvested by suction filtration with Nutsche (the TOA concentration ofthe whole filtrate was 0.4 weight %). The crystals were washed withwater and toluene, respectively, and dried in a vacuo at 40° C.overnight. Analysis by high performance liquid chromatography revealedthat the purity and rate of recovery of the crystal crop were 99% and83%, respectively.

EXAMPLE 4

To 100 g of an aqueous solution of TOA (containing 6 g of TOA) obtainedby the same procedure as Reference Example 1 was added 55% sulfuric acidunder stirring to adjust the solution to pH 8, followed by addition of25 g of toluene. While the solution was stirred at 5° C., it wasadjusted to pH 2.9 with 10% sulfuric acid (sulfuric acid was added over1 hour). The mixture was further stirred at pH 2.9 for 30 minutes, atthe end of which time the TOA crystals which had separated out wereharvested by suction filtration with Nutsche (the TOA concentration ofthe whole filtrate was not more than 0.2 weight %) . The crystals werewashed with water and toluene, respectively, and dried in a vacuo at 40°C. overnight. Analysis by high performance liquid chromatographyrevealed that the purity and rate of recovery of the crystal crop were98% and 96%, respectively.

EXAMPLE 5

To 100 g of an aqueous solution of TOA (containing 6 g of TOA) obtainedby the same procedure as Reference Example 1 was added 55% sulfuric acidunder stirring to adjust the solution to pH 8, followed by addition of17 g of toluene. While the solution was stirred at room temperature, itwas adjusted to pH 5.0 with 10% sulfuric acid (sulfuric acid was addedover 1 hour). The mixture was further stirred at pH 5 for 30 minutes, atthe end of which time the TOA crystals which had separated out wereharvested by suction filtration with Nutsche (the TOA concentration ofthe whole filtrate was 0.2 weight %). The crystals were washed withwater and toluene, respectively, and dried in a vacuo at 40° C.overnight. Analysis by high performance liquid chromatography revealedthat the purity and rate of recovery of the crystal crop were 96% and88%, respectively.

EXAMPLE 6

To 100 g of an aqueous solution of TOA (containing 4 g of TOA) obtainedby the same procedure as Reference Example 1 was added 55% sulfuric acidunder stirring to adjust the solution to pH 8, followed by addition of25 g of heptane. While the solution was stirred at room temperature, itwas adjusted to pH 3.0 with 10% sulfuric acid (sulfuric acid was addedover 1 hour). The mixture was further stirred at pH 3 for 30 minutes, atthe end of which time the TOA crystals which had separated out wereharvested by suction filtration with Nutsche (the TOA concentration ofthe whole filtrate was not more than 0.2 weight %). The crystals werewashed with water and toluene, respectively, and dried in a vacuo at 40°C. overnight. Analysis by high performance liquid chromatographyrevealed that the purity and rate of recovery of the crystal crop were95% and 97%, respectively.

EXAMPLE 7

To 100 g of an aqueous solution of TOA (containing 4 g of TOA) obtainedby the same procedure as Reference Example 1 was added 55% sulfuric acidunder stirring to adjust the solution to pH 8, followed by addition of25 g of ethyl acetate. While the solution was stirred at roomtemperature, it was adjusted to pH 3.0 with 10 % sulfuric acid (sulfuricacid was added over 1 hour). The mixture was further stirred at pH 3 for30 minutes, at the end of which time the TOA crystals which hadseparated out were harvested by suction filtration with Nutsche (the TOAconcentration of the whole filtrate was 0.6 weight %). The crystals werewashed with water and toluene, respectively, and dried in a vacuo at 40°C. overnight. Analysis by high performance liquid chromatographyrevealed that the purity and rate of recovery of the crystal crop were99% and 68%, respectively.

EXAMPLE 8

The deacylation reaction mixture obtained by the same reaction procedureas described in Reference Example 1 was cooled to room temperature andadjusted to pH about 10 with 55% sulfuric acid. The potassium sulfateseparating out was parted by suction filtration with Nutsche, followedby washing with a small quantity of 2-propanol. The solution thusobtained was subjected to solvent substitution with water under reducedpressure as in Reference Example 1 to give an aqueous solutioncontaining 6 weight % of TOA. A 4.0 g portion of this aqueous solution(containing 2.4 g of TOA) was adjusted to pH 8 with 55% sulfuric acidunder stirring, followed by addition of 8 g of 2-propanol. Then, understirring at room temperature, the solution was adjusted to pH 3.0 with10% sulfuric acid (sulfuric acid was added over 1 hour). The mixture wasfurther stirred at pH 3 for 30 minutes, at the end of which time the TOAcrystals which had separated out were harvested by suction filtrationwith Nutsche (the TOA concentration of the whole filtrate was 1.0 weight%). The crystals were washed with a 20 weight % aqueous solution of2-propanol and dried in vacuo at 40° C. overnight. Analysis by highperformance liquid chromatography revealed that the purity and rate ofrecovery of the crystal crop. were 80% and 81%, respectively.

EXAMPLE 9

In 40 g of methanol at room temperature was dissolved 10 g of a dry TOAcrystal (purity 94%) obtained by the same procedure as Example 1. Understirring at 25° C., 3 g of water was added over a quarter of one hourfor preliminary crystallization. The system was further stirred at thesame temperature for about 30 minutes to confirm the improvement ofstirring the deposited slurry (the amount of the deposited slurryobtained by preliminary crystallization was 12% and the weight ratio ofmethanol to water was 13.3). For main crystallization, 35 g of water wasfurther added over 2 hours at the same temperature. The mixture wasstirred at the same temperature for 30 minutes, at the end of which timethe TOA crystals which had separated out were harvested by filtrationwith Nutsche under reduced pressure and washed with a small quantity of50% aqueous solution of methanol (the weight ratio of methanol to waterat completion of main crystallization was 1.05). The harvested crystalcrop was dried in vacuo at 40° C. overnight. Analysis by highperformance liquid chromatography revealed that the purity and rate ofrecovery of the crystal crop were 99.2% and 87%, respectively.

EXAMPLE 10

In 40 g of 2-propanol was dissolved 10 g of a dry TOA crystal (purity94%) obtained by the same procedure as Example 1, followed by additionof 10 g of water. Then, at 25° C., 0.1 g of TOA crystals (purity 99%)obtained by the same procedure as Example 8 was added and the mixturewas stirred for 1 hour for preliminary crystallization. The system wasstirred at the same temperature for about 30 minutes to confirm the goodfacility of stirring the deposited slurry (the amount of the depositedslurry obtained by preliminary crystallization was 4 % and the weightratio of 2-propanol to water was 4.0). For main crystallization, 83 g ofwater was added over 2 hours at the same temperature. The mixture wasstirred at the same temperature for 30 minutes, at the end of which timethe TOA crystals that had separated out were harvested by suctionfiltration with Nutsche and washed with a small quantity of 30% aqueoussolution of 2-propanol (the weight ratio of 2-propanol. to water atcompletion of main crystallization was 0.43) . The harvested crystalswere dried in vacuo at 40° C. overnight. Analysis by high performanceliquid chromatography revealed that the purity and rate of recovery ofthe crystal crop were 98.8% and 81% respectively.

EXAMPLE 11

In 45 g of acetone was dissolved 10 g of a dry TOA crystal (purity 94%)obtained by the same procedure as Example 1, followed by addition of 10g of water. Then, at 25° C., 0.1 g of TOA crystals (purity 99%) obtainedby the same procedure as Example 8 were added and the system was stirredfor 1 hour for preliminary crystallization. The system was furtherstirred at the same temperature for about 30 minutes to confirm theimprovement of stirring the deposited slurry (the amount of thedeposited slurry obtained by preliminary crystallization was 10% and theweight ratio of acetone to water was 4.5). For main crystallization, 58g of water was added over 2 hours at the same temperature. The mixturewas stirred at the same temperature for 30 minutes, at the end of whichtime the TOA crystals that had separated out were harvested by suctionfiltration with Nutsche and washed with a small quantity of 40% aqueoussolution of acetone (the weight ratio of acetone to water at completionof main crystallization was 0.66). The harvested crystal crop was driedin vacuo at 40° C. overnight. Analysis by high performance liquidchromatography revealed that the purity and rate of recovery of thecrystals were 99.0% and 84%, respectively.

EXAMPLE 12

In 40 g of acetonitrile at room temperature was dissolved 4 g of a dryTOA crystal (purity 94%) obtained by the same procedure. as Example 1,followed by addition of 14 g of water. Then, at 25° C., 0.1 g of TOAcrystals (purity 99%) obtained by the same procedure as Example 8 wereadded and the system was stirred for 1 hour for preliminarycrystallization. The system was further stirred at the same temperaturefor about 30 minutes to confirm the improvement of stirring thedeposited slurry (the amount of the deposited slurry obtained bypreliminary crystallization was 8% and the weight ratio of acetonitrileto water was 2.86). For main crystallization, 146 g of water was addedover 2 hours at the same temperature. The mixture was stirred at thesame temperature for 30 minutes, at the end of which time the TOAcrystals which had separated out were harvested by suction filtrationwith Nutsche and washed with a small quantity of 30% aqueous solution ofacetonitrile (the weight ratio of acetonitrile to water at completion ofmain crystallization was 0.25). The harvested crystal crop was dried invacuo at 40° C. overnight. Analysis by high performance liquidchromatography revealed that the purity and rate of recovery of thecrystals were 99.3% and 70%, respectively.

COMPARATIVE EXAMPLE 1

An aqueous solution of TOA (containing 6 g of TOA), 100 g, obtained bythe same procedure as Reference Example 1 was adjusted to pH 8 with 55%sulfuric acid under stirring. Except for omitting the addition oftoluene, 10% sulfuric acid was added under stirring at room temperatureto adjust the solution to pH 3.0 (the addition of sulfuric acid was madeover 1 hour) in the same manner as in Example 1. As a result, a yellowoil was separated out and substantially no crystal crop could beharvested by suction filtration with Nutsche, indicating that thedescribed procedure does not yield a crystal crop that might beharvested by filtration.

COMPARATIVE EXAMPLE 2

In 40 g of methanol at room temperature was dissolved 10 g of a dry TOAcrystal (purity 94%) obtained by the same procedure as Example 1. When40 g of water was continuously added over about 20 minutes understirring at 25° C., the system became hardly stirrable in the course ofcrystallization, indicating that when the crystallization is carried outwithout omitting a preliminary crystallization, good crystals can hardlybe obtained with good commercial workability.

INDUSTRIAL APPLICABILITY

In accordance with the present invention, the compound (1) of highquality can be directly obtained as crystals from the reaction mixturein a simple manner and in good yield and that the compound (1) can bepurified by recrystallization to higher grade at a good recovery rate.

1-41. (canceled)
 42. A method for crystallization of a compound (1) of the following general formula (1):

in which R is CH₃, CH₂OH, (CH₂OCOR¹, CO₂R², CONR³R⁴, OH, CH₂OR¹ or CH₂NR³R⁴; R¹ is a C₁₋₅ alkyl group; R² is H or a C₁₋₅ alkyl group; R³ and R⁴ are independently selected from among H and C₁₋₅ alkyl groups; a and b each is a double bond, one of a and b is a single bond with the other being a double bond or a and b each is a single bond, by mixing a solution of the compound (1) in a water-miscible good solvent with water, in which a slurry with a necessary suspension amount of the compound (1) for inhibiting oil formation and scaling of the compound (1) is prepared in advance and a main crystallization is then carried out in the presence of said slurry.
 43. The method for crystallization according to claim 42, wherein the necessary suspension amount is not more than 30 weight % based on the total amount of compound (1) at completion of main crystallization.
 44. The method for crystallization according to claim 42, wherein the slurry is prepared by preliminary crystallization or addition of crystals of compound (1).
 45. The method for crystallization according to claim 42, wherein the mixing of the solution of compound (1) in a water-miscible good solvent with water is carried out by adding water to said solution of compound (1) in the water-miscible good solvent.
 46. The method for crystallization according to claim 45, wherein the addition of water to the solution of compound (1) in a water-miscible good solvent for preliminary crystallization is carried out in such a manner that the weight ratio of said water-miscible good solvent to water will be 0.1 to
 20. 47. The method for crystallization according to claim 42, wherein the mixing of the solution of compound (1) in a water-miscible good solvent with water is carried out by adding said solution of compound (1) in the water-miscible good solvent to water.
 48. The method for crystallization according to claim 47, wherein the addition of said solution of compound (1) in a water-miscible good solvent to water for preliminary crystallization is carried out in such a manner that the weight ratio of the water-miscible good solvent to water will not be greater than
 1. 49. The method for crystallization according to claim 45, wherein the addition of said solution of compound (1) in a water-miscible good solvent or water is carried out either continuously or portion wise.
 50. The method for crystallization according to claim 42, wherein the temperature for preliminary crystallization is not higher than 70° C.
 51. The method for crystallization according to claim 42, wherein the temperature for preliminary crystallization is 0 to 50° C.
 52. The method for crystallization according to claim 42, wherein the temperature for main crystallization is not higher than 70° C.
 53. The method for crystallization according to claim 52, wherein the crystal crop is increased by cooling the main crystallization system to a final temperature of not over 30° C.
 54. The method for crystallization according to claim 42, wherein the weight ratio of the water-miscible good solvent to water at completion of main crystallization is 0.01 to
 2. 55. The method for crystallization according to claim 42, wherein the solution of compound (1) in a water-miscible good solvent is either a solution obtainable by neutralizing the reaction solution resulting from deacylation of a compound (2) of the following general formula (2):

wherein R, a

removing the precipitated salt or other precipitate by filtration, or a solution obtainable by subjecting said reaction solution to concentration or solvent substitution.
 56. The method for crystallization according to claim 55, wherein an impurity or color contaminant by-produced in the deacylation reaction is removed with an adsorbent in advance of crystallization.
 57. The method for crystallization according to claim 55, wherein the deacylation reaction solvent doubles as the water-miscible good solvent for said solution of compound (1) in a water-miscible good solvent.
 58. The method for crystallization according to claim 42, wherein the water-miscible good solvent is a solvent selected from among C₁₋₆ saturated alcohols represented by C_(n)H_(2n+2)O, C₁₋₈ saturated diols represented by C_(n)H_(2n+2)O₂, C₁₋₈ saturated triols represented by C_(n)H_(2n+2)O₃, C₃₋₅ ketones represented by C_(n)H_(2n)O, ethers, and nitriles.
 59. The method for crystallization according to claim 42, wherein the water-miscible good solvent is a solvent selected from among methanol, ethanol, 1-propanol, 2-propanol, butanol, 2-butanol, 2-methylpropanol, tert-butanol, 2-methylbutanol, 1,2-ethanediol, 1,3-propanediol, 1,5-pentanediol, acetone, methyl ethyl ketone, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and acetonitrile or a mixture of two or more such solvents.
 60. The method for crystallization according to claim 42, wherein the water-miscible good solvent is a solvent selected from among methanol, ethanol, 1-propanol, 2-propanol, acetone, and acetonitrile or a mixture of two or more such solvents.
 61. The method for crystallization according to claim 42, wherein the water-miscible good solvent is a solvent selected from among methanol, 2-propanol, acetone, and acetonitrile or a mixture of two or more such solvents. 